POS1185 HIGH PHENOTYPIC VARIABILITY IN THREE SIBLINGS WITH ADA2 DEFICIENCY
Authors: E. Sculco, K. Paciaroni, E. Sangiorgi, I. Quinti, F. Pulvirenti
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Deficiency of adenosine deaminase 2 (DADA2) is a monogenic disease caused by biallelic mutations in the ADA2 gene. The phenotypic spectrum is broad, most commonly including fever, early-onset vasculitis, stroke, and hematologic dysfunction. Initially considered a childhood disease, the first presentation is now being reported well into adulthood. Vasculitis manifestations closely resemble polyarteritis nodosa, with livedo reticularis, racemosa-like skin rash, and central nervous system involvement with ischemic or hemorrhagic stroke. Immunological manifestations include hypogammaglobulinemia and recurrent infections. Currently, TNF inhibitors are the treatment of choice to reduce the risk of vascular events and control inflammation but seem not effective for immunodeficiency and haematological manifestations, which require hematopoietic stem cell transplantation. <h3>Objectives</h3> To describe the clinical features, genotype, and treatment approaches of subjects bearing the same ADA2 homozygous pathogenic variant, but presenting a different clinical expression. <h3>Methods</h3> To describe the clinical features, genotype, and treatment approaches of subjects bearing the same ADA2 homozygous pathogenic variant, but presenting a different clinical expression. <h3>Results</h3> The proband was a 57 years-old female with severe neutropenia and recurrent infection, born out of consanguineous marriage. Her past medical history was characterized by recurrent episodes of fever during childhood. At the age of 18, she developed erythema nodosum, the purpura of her limbs, and arthritis of the hands and feet treated with steroids. In her forties, the fever became more recurring and she suffered from recurrent vaginitis by Candida albicans, worsening pyorrea and oral ulcers, with tooth loss. At 50 years, she was diagnosed with diabetes mellitus needing insulin treatment. At 57 years, she was referred to the hematologic unit for severe neutropenia and she started treatment with granulocyte colony-stimulating factor. When he was referred to our hospital, she was afebrile with stable vital signs. Laboratory tests showed severe neutropenia, with normal acute-phase reactants. The bone marrow smear documented a late maturation arrest, with an increased number of cytotoxic lymphocytes CD3+CD8+. Autoantibody-panel including ANA, anti–double–stranded DNA and ENA antibodies were negative, and the rheumatoid factor was positive. The patient's family history was positive for a 62 years-old brother with a prior left thalamic nucleus haemorrhage, a 57-year-old sister with severe hypogammaglobulinemia and neutropenia, recurrent fever and livedo reticularis, and one sister who died at 47 from a heart attack. Exome analysis identified the proband and her siblings as homozygous for the (c.746T&gt;C p(Leu249Pro) (NM_001282225) variant of the ADA2 gene (OMIM:607575). Anti-TNF treatment was proposed for all patients and immunoglobulin treatment was prescribed for the sister with hypogammaglobulinemia. Despite being informed of the risk, all the patients declined the treatment. <h3>Conclusion</h3> This familiar case demonstrated the wide range of phenotypic variability in DADA2. The search for ADA2 mutations and the assessment of ADA2 activity should be considered with the familiar history positive for the association of hypogammaglobulinemia, inflammatory conditions, and stroke, even if in different relatives. Familiar cases of DADA2 provide a unique insight into its disease's wide range of phenotypic variability. Further studies are needed to determine differences in the underlying pathophysiology of different phenotypes in DADA2. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.